The present invention relates to methods useful in combating Pneumocystis carinii pneumonia and prodrug compounds useful therefor.
Pentamidine is used for the treatment of Pneumocystis carinii pneumonia, or xe2x80x9cPCPxe2x80x9d. The importance of pentamidine has dramatically escalated recently due to the marked increase of patients suffering from PCP. The increase in the afflicted patient population is an unfortunate consequence of the increasing presence of the Acquired Immunodeficiency Syndrome (xe2x80x9cAIDSxe2x80x9d). It is now estimated that approximately 70 percent of AIDS patients contract PCP. Because of the high incidence of PCP in AIDS patients, pentamidine has found utility not only in the treatment of PCP, but also as prophylaxis, in preventing or delaying the initial onset or recurrence of PCP, especially in AIDS patients. Currently, pentamidine is most commonly administered as a therapeutic agent by intravenous infusion and as a prophylactic agent by aerosol dosage.
However, an unfortunate side effect of pentamidine is its toxicity. Some fatalities have been attributed to severe hypotension, dysglycemia, and cardiac arrhythmias in patients treated with pentamidine. Contrawise, insufficient dosage may result in dissemination of disease beyond the lung, an occurrence which is associated with a poor prognosis. Therapeutic drug monitoring is not used because of the cost and complexity of the currently available assay techniques which require the extraction of plasma and High Performance Liquid Chromatography (HPLC) analysis. As a result, the toxicity of pentamidine is a significant concern, which is driving the market toward the development of pentamidine substitutes capable of avoiding or minimizing the undesirable side effects associated with the use of pentamidine. See, e.g., J. Spychala et al., Eur. J. Med. Chem. 29, 363-367 (1994); I. O. Donkor et al., J. Med. Chem. 37, 4554-4557 (1994); R. R. Tidwell et al., J. Protozool. 6, 148S-150S (1991).
Accordingly, it is an object of the present invention to provide new compounds useful in the treatment of P. carinii pneumonia.
A method of treating Pneumocystis carinii pneumonia in a subject in need of such treatment is disclosed. The method comprises orally administering to the subject a bis-benzamidoxime, derivative thereof, or a pharmaceutically acceptable salt thereof (hereinafter referred to as the xe2x80x9cactive compoundxe2x80x9d), that is reduced in the subject to produce a benzamidine having anti-P. carinii activity. The method of the present invention may alternatively comprise intravenously administering to the subject an active compound as disclosed herein.
A second aspect of the present invention is a pharmaceutical formulation comprising, in combination with a pharmaceutically acceptable carrier, a bis-benzamidoxime, or a pharmaceutically acceptable salt thereof, that is reduced in a mammalian subject after administration thereto to produce a benzamidine having anti-Pneumocystis carinii activity, subject to the proviso that said bis-benzamidoxime is not 1,5-bis(4xe2x80x2-(N-hydroxyamidino)phenoxy) pentane.
A third aspect of the present invention are active compounds useful in carrying out a therapeutic method of the present invention.
A fourth aspect of the present invention is the use of an active compound as disclosed herein for the manufacture of a medicament useful in carrying out a therapeutic method of treatment as given above.